Modern therapeutic concepts for the treatment of tumors and particularly therapeutic concepts involving immune modulating agents involve considerable costs and often adverse side effects for the patient. Additionally not only one but several options for therapy or even due to bad prognostic effect the option of not actively treating the tumor but taking only palliative care of the patient must be considered by the physician. Hence selecting the most optimal therapeutic concept by taking into consideration predictive parameters is of high importance.
Several predictive or prognostic factors are known in the art and are used by the physicians:                clinical-morphological criteria: TNM classification, R classification        histopathological criteria: histological grade of differentiation        molecular factors related to the target structures of tumor therapy: rate of expression of receptors (e.g. Her2/neu—Trastuzumab) and molecular status of mutation (KRAS mutation—Cetuximab).        
Widely used in the field of diagnostics and the surveillance of the effects of therapeutic developments e.g. in the treatment of infectious diseases, anemic diseases and leukemia is the determination of the white cell blood count (also called blood differential test). The blood differential test measures the percentage of each type of white blood cell (also called leukocytes). This complete white blood cell count, which includes a lymphocyte count (ALC and RLC), is part of normal diagnosis and is an inexpensive, non-sophisticated and universally available test. Five types of leukocytes normally appear in the blood, i.e. neutrophils (normal values from adults: 40% to 60%,) lymphocytes (15% to 40%), monocytes (2% to 8%), eosinophils (1% to 4%), basophils (0.5% to 1%).
Generally all kind of acute stress and all kind of infections raise the number of leukocytes. Abnormally high titers of leukocytes are seen inter alia during inflammation, immunological reactions and leukemia. Changes in the blood differential test results are caused by the increase of one type of white blood cells which causes a decrease in the proportion of the remaining types of white blood cells.
Thus, an increased RLC above normal ranges may be due to an acute stage of viral infection, connective tissue disease, hyperthyroidism, Addison's disease and splenomegaly) (Tefferi et al., Mayo Clin. Proc. 80:923, 2005). Moreover, it is normal that children younger than 2 years have increased RLC. On the opposite side, a decreased RLC could be attributed to e.g. AIDS, bone marrow suppression, aplastic anemia, neoplasms, steroids, adrenocortical hyperfunction, neurologic disorders (multiple sclerosis, myasthenia gravis, Guillain Barre syndrome) (Tefferi et al., Mayo Clin. Proc. 80:923, 2005), administration of steroid compounds and chronic inflammation reflecting a suppression of the immune system caused by said diseases.
Considering this, the blood differential test and the changes of the proportion of the individual components of white blood cells can be understood as a highly suitable method for monitoring the immunological status of an individual reflecting the relation of immunostimulatory and immunosuppressive factors.
In view of the importance of immunological parameters in cancer development and tumor progression, US 2010/0028932 and the underlying publication teach that baseline absolute lymphocyte counts (ALC) prior to therapeutic onset significantly influence overall survival of tumor patients. It provides methods for the prognostic impact of ALC and AGC (absolute granulocyte counts) on the overall survival of tumor patients independent of any particular medical treatment.
One important method for activating immune cells is administration of antibodies which are directed against a tumor-specific antigen, One example for the beneficial use of antibodies is administration of trifunctional bispecific (Triomab) antibodies which are characterized in that they bind at the same time (i) to the T cell receptor complex of a T cell, (ii) to tumor-associated antigens on a tumor cell, and (iii) via the Fc-portion of the trifunctional antibody, to Fcgamma-receptor I, IIa and/or III positive cells for the induction of anti-tumor immunity in humans and animals. They are described e.g. in U.S. Pat. No. 6,551,592. It is well-established knowledge that cytotoxic T cells stimulated by anti-CD3 triggering and co-stimulatory CD28-B7 interaction (i.e. via interplay of T cells and activating Fcgamma-receptor positive accessory cells) are the most important effector cells in the elimination of malignant target cells due to trifunctional bispecific antibodies. Furthermore, it is well-accepted that the mitogenic anti-CD3 binding arm of trifunctional antibodies together with co-stimulatory signals (delivered by accessory cells) evokes T cell activation subsequently followed by prominent T cell stimulation and/or T cell proliferation. These hematopoietic changes are central to the activity of mitogenic anti-CD3 antibodies as demonstrated by e.g. Schneider et al., Stem Cells 15:154, 1997.
Nevertheless, US 2010/0028932 neither gives any evidence on the role RLC and RGC might play in the development of tumor diseases nor describes predictive factors for beneficially using therapeutic interventions that clearly stimulate the T cell arm of cell-mediated immune responses against cancer.
It is an object of the present invention to provide reliable predictive factors for the benefit of an intervention of tumor patients by an immune therapy which is capable of activating immune cells.